Klein Luiz Carlos, Passos Carolina Santos Dos, Moraes Aline Pereira, Wakui Vinicius Galvao, Konrath Eduardo Luis, Nurisso Alessandra, Carrupt Pierre-Alain, de Oliveira Cecilia Maria Alves, Kato Lucilia, Henriques Amelia Teresinha
Programa de Pos Graduacao em Ciencias Farmaceuticas, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, 90610-000 Porto Alegre - RS, Brazil.
Curr Top Med Chem. 2014;14(8):1056-75. doi: 10.2174/1568026614666140324142409.
Indole alkaloids and synthetic indole derivatives are well known for their therapeutic importance. In fact, preclinical and clinical studies had already demonstrated several pharmacological activities for these compounds. Here, we overview the multifunctional potential of these molecules for the inhibition of enzymes related to neurodegenerative disease: acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases A and B (MAO-A and MAO-B). A focus will be given on Psychotria L. genus, considering its reported central effects. Finally, three Psychotria alkaloids, namely desoxycordiofoline (61), bahienoside A (64) and bufotenine (65), along with the synthetic indole derivatives (5S)- 5-(1H-indol-3-ylmethyl)imidazolidine-2,4-dione (66), 5-(1H-indol-3-ylmethyl)-2-thioxoimidazolin-4-one (67), 5-(1Hindol- 3-ylmethyl)-3-methyl-2-thioxoimidazolidin-4-one (68), and methyl 2-(aminoN-(2-(4-methylcyclohex-3-enyl)propan- 2-yl)methanethioamino)-3-(1H-indol-3-yl)propanoate (69), were evaluated in vitro regarding their interactions with AChE, BChE, MAO-A and MAO-B. It was observed that 66 and 68 were able to inhibit MAO-A activity with IC50 value of 8.23 and 0.07 μM. Molecular docking calculations were performed in order to understand the interactions between both ligands (66 and 68) and MAO-A. It was observed that the indole scaffold of both compounds bind into the MAO-A active site in the same orientation, establishing van der Waals contacts with lipophilic amino acids. Additionally, the hydantoin ring of 66 is able to interact by hydrogen bonds with two conserved water molecules in the MAO-A active site, while the methyl-thiohydantoin ring of 68 is within hydrogen bond distance from the hydrogen atom attached to the (N-5) of FAD cofactor. Taking together, our findings demonstrate that the indolyl-hydantoin and indolylmethyl-thiohydantoin rings might consists of good scaffolds for the development of new MAO-A inhibitors possessing neuroprotective properties.
吲哚生物碱和合成吲哚衍生物因其治疗重要性而闻名。事实上，临床前和临床研究已经证明了这些化合物的多种药理活性。在此，我们概述了这些分子对与神经退行性疾病相关的酶的抑制作用的多功能潜力：乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BChE）、单胺氧化酶A和B（MAO-A和MAO-B）。鉴于其已报道的中枢作用，将重点关注九节属植物。最后，对三种九节生物碱，即去氧可多福林（61）、巴伊诺苷A（64）和蟾蜍特宁（65），以及合成吲哚衍生物（5S）-5-（1H-吲哚-3-基甲基）咪唑烷-2,4-二酮（66）、5-（1H-吲哚-3-基甲基）-2-硫代咪唑啉-4-酮（67）、5-（1H-吲哚-3-基甲基）-3-甲基-2-硫代咪唑烷-4-酮（68）和2-（氨基-N-（2-（4-甲基环己-3-烯基）丙烷-2-基）甲硫基氨基）-3-（1H-吲哚-3-基）丙酸甲酯（69），就它们与AChE、BChE、MAO-A和MAO-B的相互作用进行了体外评估。观察到66和68能够抑制MAO-A活性，IC50值分别为8.23和0.07μM。进行了分子对接计算，以了解两种配体（66和68）与MAO-A之间的相互作用。观察到这两种化合物的吲哚支架以相同方向结合到MAO-A活性位点，与亲脂性氨基酸建立范德华接触。此外，66的乙内酰脲环能够通过氢键与MAO-A活性位点中的两个保守水分子相互作用，而68的甲硫基乙内酰脲环与附着在FAD辅因子（N-5）上的氢原子的距离处于氢键距离范围内。综上所述，我们的研究结果表明，吲哚基乙内酰脲和吲哚基甲基硫代乙内酰脲环可能是开发具有神经保护特性的新型MAO-A抑制剂的良好支架。
